Article

Comparative studies evaluating mouse models used for efficacy testing of experimental drugs against Mycobacterium tuberculosis.

Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.45). 12/2010; 55(3):1237-47. DOI: 10.1128/AAC.00595-10
Source: PubMed

ABSTRACT Methodologies for preclinical animal model testing of drugs against Mycobacterium tuberculosis vary from laboratory to laboratory; however, it is unknown if these variations result in different outcomes. Thus, a series of head-to-head comparisons of drug regimens in three commonly used mouse models (intravenous, a low-dose aerosol, and a high-dose aerosol infection model) and in two strains of mice are reported here. Treatment with standard tuberculosis (TB) drugs resulted in similar efficacies in two mouse species after a low-dose aerosol infection. When comparing the three different infection models, the efficacies in mice of rifampin and pyrazinamide were similar when administered with either isoniazid or moxifloxacin. Relapse studies revealed that the standard drug regimen showed a significantly higher relapse rate than the moxifloxacin-containing regimen. In fact, 4 months of the moxifloxacin-containing combination regimen showed similar relapse rates as 6 months of the standard regimen. The intravenous model showed slower bactericidal killing kinetics with the combination regimens tested and a higher relapse of infection than either aerosol infection models. All three models showed similar outcomes for in vivo efficacy and relapse of infection for the drug combinations tested, regardless of the mouse infection model used. Efficacy data for the drug combinations used also showed similar results, regardless of the formulation used for rifampin or timing of the drugs administered in combination. In all three infection models, the dual combination of rifampin and pyrazinamide was less sterilizing than the standard three-drug regimen, and therefore the results do not support the previously reported antagonism between standard TB agents.

1 Follower
 · 
94 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dose selection for rifampin in the treatment of active pulmonary tuberculosis (TB) illustrates some of the challenges for dose optimization within multidrug therapies. Rifampin-based anti-TB regimens are often combined with antiretroviral therapies to treat human immunodeficiency virus (HIV) coinfection. The potent cytochrome P450 (CYP) enzyme inducing properties of rifampin give rise to significant drug-drug interactions, the minimization of which by limiting the dose, conflicts with the maximization of bacterial killing by increasing the dose. Such multiple and conflicting objectives lead to a set of trade-off optimal solutions for dose optimization rather than a single best solution. Here, we combine pharmacokinetic/pharmacodynamic (PK/PD) modeling with multiobjective optimization to quantitatively explore trade-offs between therapeutic and adverse effects of optimal dosing for the example of rifampin in TB-infected mice. The PK/PD model describes rifampin concentrations in plasma and liver following oral administration together with hepatic CYP enzyme induction and bacterial killing kinetics. We include optimization objectives descriptive of antimicrobial efficacy, CYP-mediated drug-drug interactions, and drug exposure-dependent toxicity. Results show non-conventional dosing scenarios that allow for increased efficacy relative to uniform dosing without increasing drug-drug interactions. Additionally, we find currently employed dosages for rifampin to be nearly optimal with respect to trade-offs between efficacy and toxicity. While limited by the accuracy and applicability of the PK/PD model, these results provide an avenue for experimental investigation of complex dose optimization problems. This method can be extended to include additional drugs and optimization objectives, and may provide a useful tool for individualized medicine.
    Journal of Pharmacokinetics and Pharmacodynamics 08/2014; 41(6). DOI:10.1007/s10928-014-9380-2 · 1.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mycobacterium tuberculosis is considered one of the most successful pathogens and drug resistant Tuberculosis (MDRTB) a disease that urgently requires new chemical entities to be developed for treatment. There are currently several new molecules under clinical investigation in the TB drug development pipeline. However the complex lifestyle of M. tuberculosis within the host presents a barrier to the development of new drugs. In this review, we highlight the reasons that make TB drug discovery and development challenging as well as providing solutions, future directions and alternative approaches to new therapeutics for TB. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 03/2015; DOI:10.1111/cbdd.12549 · 2.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Robust and physiologically relevant infection models are required to investigate pharmacokinetic-pharmacodynamic (PK/PD) correlations for anti-tuberculosis agents at preclinical discovery. We have validated an inhalation-based rat infection model of tuberculosis harbouring mycobacteria in a replicating state, that is suitable for investigating pharmacokinetics and drug action of anti-tubercular agents. A reproducible and actively replicating lung infection was established in Wistar rats by inhalation of a series of graded inocula of M.tuberculosis. Following an initial instillation of ∼105 log10CFU/lung, M.tuberculosis grew logarithmically for the first 3 weeks, and then entered into a chronic phase with no net increase in pulmonary bacterial loads. Dose response of front line anti-TB drugs was investigated following pharmacokinetic measurements in the plasma of infected rats. Rifampicin, Isoniazid, and Ethambutol dosed per orally exhibited bactericidality and good dose response with maximal effect of 5.66, 4.66, and 4.80 log10CFU reductions in the lungs, respectively. In contrast, Pyrazinamide was merely bacteriostatic with 1.92 log10CFU reduction and did not reduce the bacterial burden beyond the initial bacterial loads present at beginning of treatment in spite of high Pyrazinamide blood levels. Rat infection model with actively replicating bacilli provides a physiologically distinct and pharmacologically relevant model that can be exploited to distinguish investigational compounds in to bacteriostatic or bactericidal scaffolds. We propose that this rat infection model though need more drug substance, can be used in early discovery settings to investigate pharmacology of novel anti-tubercular agents for the treatment of active pulmonary tuberculosis.
    Tuberculosis (Edinburgh, Scotland) 05/2014; 94(3). DOI:10.1016/j.tube.2014.02.004 · 3.50 Impact Factor